Neurotransmission mediated by gamma-aminobutyric acid type A (GABA(A)) receptors in the mammalian medial preoptic area (mPOA) plays a pivotal role in the expression of hormone-sensitive behaviors. Hand in hand with GABAergic control of reproduction, hormone treatments that activate gonadal steroid signaling pathways in gonadectomized rats are known to regulate the expression of specific GABA(A) receptor subunit mRNAs. While the effects of exogenous hormone treatments have been well documented, little information is available as to how GABA(A) receptor-mediated transmission in the mPOA is altered by endogenous changes in hormonal state in gonadally-intact adult animals or if those changes can be ascribed to hormone-dependent changes in receptor subunit composition. In the present study, we found that both the peak amplitudes of GABA(A) receptor-mediated synaptic currents in the mPOA, as well as the ability of the endogenous neurosteroids to modulate those currents, varied as a function of the estrous cycle. Moreover, we found that the degree of neurosteroid modulation was also significantly different between wild-type and the androgen-insensitive testicular feminization (Tfm) mutant male mice. Semiquantitative RT-PCR analysis performed to assess levels of GABA(A) receptor subunit mRNAs indicated that levels of specific subunits varied over the course of the estrous cycle and between wild-type and Tfm male mice. The variations in GABA(A) receptor expression and function in the mPOA that are associated with differences in gonadal steroid signaling may contribute to the dynamic nature of GABAergic control of neuroendocrine pathways.
Anabolic-androgenic steroids (AAS) have become significant drugs of abuse in recent years with the highest increase reported in adolescent girls. In spite of the increased use of AAS, the CNS effects of these steroids are poorly understood. We report that in prepubertal female rats, three commonly abused AAS, 17alpha-methyltestosterone, stanozolol, and nandrolone, induced rapid and reversible modulation of GABAergic currents in neurons of two brain regions known to be critical for the expression of reproductive behaviors: the ventromedial nucleus of the hypothalamus (VMN) and the medial preoptic area (mPOA). All three AAS significantly enhanced peak synaptic current amplitudes and prolonged synaptic current decays in neurons of the VMN. Conversely all three AAS significantly diminished peak current amplitudes of synaptic currents from neurons of the mPOA. The endogenous neuroactive steroids, 3alpha-hydroxy-5alpha-pregnan-20-one and 5alpha-androstane-3alpha,17beta-diol, potentiated currents in the VMN as did the AAS. In contrast to the negative modulation induced by AAS in the mPOA, the endogenous steroids potentiated responses in this region. To determine the concentration response relationships, modulation by the AAS, 17alpha-methyltestosterone (17alpha-meT), was assessed for currents evoked by ultrafast perfusion of brief pulses of GABA to acutely isolated neurons. Half-maximal effects on currents elicited by 1 mM GABA were elicited by submicromolar concentrations of AAS for neurons from both brain regions. In addition, the efficacy of 10(-5) to 10(-2) M GABA was significantly increased by 1 microM 17alpha-meT. Previous studies have demonstrated a striking dichotomy in receptor composition between the VMN and the mPOA with regard to gamma subunit expression. To determine if the preferential expression of gamma(2) subunit-containing receptors in the VMN and of gamma(1) subunit-containing receptors in the mPOA could account for the region-specific effects of AAS in the two regions, responses elicited by ultrafast perfusion of GABA to human embryonic kidney 293 cells transfected with alpha(2), beta(3), and gamma(2) or alpha(2), beta(3), and gamma(1) subunit cDNAs were analyzed. As with native VMN neurons, positive modulation of GABA responses was elicited for alpha(2)beta(3)gamma(2) recombinant receptors, while negative modulation was induced at alpha(2)beta(3)gamma(1) receptors as in the mPOA. Our data demonstrate that AAS in doses believed to occur in steroid abusers can induce significant modulation of GABAergic transmission in brain regions essential for neuroendocrine function. In addition, the effects of these steroids can vary significantly between brain regions in a manner that appears to depend on the subunit composition of GABA(A) receptors expressed.
Studies with canagliflozin, in subjects with type 2 diabetes, have shown that its use is associated with reductions in HbA1c and body weight and small reductions in blood pressure and triglycerides, while increasing high-density lipoprotein cholesterol and low-density lipoprotein cholesterol. As monotherapy in Japanese subjects, or in comparison with glimepiride in CANTATA-SU (CANagliflozin Treatment and Trial Analysis versus SUlphonylurea), canagliflozin causes a low incidence of hypoglycemia, and this is an advantage over glimepiride. However, one of the disadvantages with canagliflozin, which was also highlighted in CANTATA-SU, is that canagliflozin can cause urogenital infections, which are not observed with other antidiabetic drugs. The Federal Drug Administration has recently approved canagliflozin for use in type 2 diabetes, while directing that a clinical outcome safety trial be undertaken. We are concerned that canagliflozin has been approved for use in type 2 diabetes prior to a clinical outcome study of efficacy being undertaken and without the outcome of further safety testing.
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